(conjugated estrogens/bazedoxifene)
14 CLINICAL STUDIES
14 CLINICAL STUDIES
14.1 Treatment of Moderate to Severe Vasomotor Symptoms Associated with Menopause in Women with a Uterus
The safety and efficacy of DUAVEE as a treatment for moderate to severe vasomotor symptoms associated with menopause was established in a 12-week randomized, double-blind, placebo-controlled study (Study 3). Study 3 enrolled a total of 318 women, age 42–64 (mean age of 53 years), who had at least 7 moderate to severe hot flushes per day or at least 50 per week at baseline. The mean number of years since menopause was 4.5 years with all women undergoing natural menopause. A total of 127 women were assigned to DUAVEE and 63 women were assigned to placebo.
In Study 3, DUAVEE significantly reduced the number and severity of moderate to severe hot flushes, as measured by the daily severity score, compared with placebo at Weeks 4 and 12. The change from baseline in the number and severity of moderate to severe hot flushes observed and the difference from placebo in Study 3 are shown in Table 3.
| Frequency | Severity | |||
|---|---|---|---|---|
| DUAVEE | Placebo | DUAVEE | Placebo | |
N | 122 | 63 | 122 | 63 |
Baseline | 10.3 | 10.5 | 2.3 | 2.3 |
Week 4 | ||||
Mean Change* | -5.9 | -2.8 | -0.6 | -0.1 |
Treatment Difference† | -3.1 (-4.4, -1.7)‡ | -- | -0.5 (-0.7, -0.3)‡ | -- |
Week 12 | ||||
Mean Change* | -7.6 | -4.9 | -0.9 | -0.3 |
Treatment Difference† | -2.7 (-3.8, -1.6)‡ | -- | -0.6 (-0.9, -0.4)‡ | -- |
14.2 Prevention of Postmenopausal Osteoporosis in Women with a Uterus
The safety and efficacy of DUAVEE for the prevention of postmenopausal osteoporosis was demonstrated in Study 1 and Study 2.
Study 1 was a 24-month, double-blind, randomized, placebo- and active-controlled study evaluating the safety and efficacy of multiple combinations of conjugated estrogen/bazedoxifene (including conjugated estrogens 0.45 mg/bazedoxifene 20 mg) compared to placebo. The primary endpoint of the study was the incidence of endometrial hyperplasia at Year 1. Bone mineral density change at the lumbar spine at Year 2 was the key secondary endpoint, assessed in two subsets of patients (Substudy I and Substudy II). Patients enrolled into Substudy I had to be more than 5 years postmenopausal, have a lumbar spine or total hip T-score of -1 to -2.5, and have at least one additional risk factor for osteoporosis (e.g., Caucasian race, family history of osteoporosis, early menopause, thin/small frame, inactive lifestyle, tobacco abuse). Those enrolled into Substudy II had to be 1–5 years postmenopausal with at least one additional risk factor for osteoporosis. A total of 3,397 women age 40–75 (mean age of 56 years) were enrolled in the overall study. Substudy I enrolled a total of 1,454 women (182 women receiving DUAVEE) with mean baseline T-scores of -1.43 and -1.52 in the DUAVEE and placebo groups, respectively. Substudy II enrolled a total of 861 women (with 111 women receiving DUAVEE) with mean baseline T-scores of -0.81 and -0.94 in the DUAVEE and placebo groups, respectively. Women also took calcium (600–1200 mg) and vitamin D (200–400 IU) daily.
In these substudies, treatment with DUAVEE significantly increased lumbar spine bone mineral density (BMD) at 24 months compared to placebo in both groups of postmenopausal women (Table 4).
| DUAVEE | Placebo | |
|---|---|---|
| ** Adjusted mean changes, confidence intervals, and p-values based on an ANCOVA model with treatment and region (U.S. or non-U.S.) as factors and baseline BMD value and years since menopause as covariates using the Modified Intention to Treat population with Last Observation Carried Forward. Study 1 excludes those subjects with missing source documentation. | ||
| ||
Between 1 and 5 Years Postmenopausal | ||
N | 95 | 95 |
% Mean Change | 1.72 | -1.90 |
Difference from Placebo (95% C.I.) | 3.62 (2.64, 4.60)* | |
More Than 5 Years Postmenopausal | ||
N | 155 | 151 |
% Mean Change | 1.64 | -1.47 |
Difference from Placebo (95% C.I.) | 3.11 (2.29, 3.93)* | – |
In Study 1, treatment with DUAVEE also significantly increased total hip BMD. The treatment difference (or difference from placebo) in total hip BMD at 24 months was 1.96% (DUAVEE minus placebo) in women who had been postmenopausal between 1 and 5 years and 1.73% (DUAVEE minus placebo) in women who had been postmenopausal for more than 5 years.
Study 2 was a 12-month, double-blind, randomized, placebo- and active-controlled study. The primary endpoint was the incidence of endometrial hyperplasia at 12 months. The prevention of osteoporosis was assessed in a substudy that enrolled women (n=590) who were less than 5 years postmenopausal (mean 2.5 years). The mean baseline T-score in the substudy was -0.91 in the DUAVEE group and -0.95 in the placebo group. The mean age of women (n=135) taking DUAVEE was 53 years (range 46–60 years). Women also took calcium (600 mg) and vitamin D (400 IU) daily.
In Study 2, treatment with DUAVEE significantly increased mean lumbar spine BMD (treatment difference, 1.51%), at 12 months compared to placebo in women who had been postmenopausal between 1 and 5 years. Treatment with DUAVEE also increased total hip BMD. The treatment difference in total hip BMD at 12 months was 1.21%.
14.3 Effects on the Endometrium
Effects of DUAVEE on endometrial hyperplasia and endometrial malignancy were assessed in Study 1 and Study 2. The Efficacy Evaluable population included patients who had taken at least one dose of DUAVEE, had baseline and post baseline endometrial biopsies, or had been diagnosed with hyperplasia. By endometrial biopsy, the incidence of endometrial hyperplasia or malignancy for DUAVEE was below 1% in both studies (see Table 5).
| STUDY 1* | STUDY 2* | ||||
|---|---|---|---|---|---|
| Treatment Group | Month | % (n/N) | 1 – Sided 95% UL | % (n/N) | 1 – Sided 95% UL |
| UL = Upper limit | |||||
| |||||
DUAVEE | 12 | 0.00% (0/336) | 0.89 | 0.30% (1/335) | 1.41 |
24 | 0.68% (2/294) | 2.13 | -- | -- | |
14.4 Effects on Uterine Bleeding and Spotting
Uterine bleeding or spotting were evaluated in two clinical studies (Studies 1 and 2) by daily diary. In Study 1, cumulative amenorrhea at Year 1 was 83% in women treated with DUAVEE and 85% in women who received placebo. In Study 2, cumulative amenorrhea at Year 1 was 88% in women treated with DUAVEE and 84% in women who received placebo.
14.5 Women's Health Initiative Studies
The WHI enrolled approximately 11,000 predominantly healthy postmenopausal women to assess the risks and benefits of daily oral conjugated estrogens 0.625 mg compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of CHD (defined as nonfatal MI, silent MI and CHD death), with invasive breast cancer as the primary adverse outcome. A "global index" included the earliest occurrence of CHD, invasive breast cancer, stroke, PE, colorectal cancer, hip fracture, or death due to other cause. These substudies did not evaluate the effects of conjugated estrogens on menopausal symptoms.
The WHI estrogen-alone substudy was stopped early because an increased risk of stroke was observed, and it was deemed that no further information would be obtained regarding the risks and benefits of estrogen-alone in predetermined primary endpoints.
Results of the estrogen-alone substudy, which included 10,739 women (average 63 years of age, range 50 to 79; 75.3 percent White, 15.1 percent Black, 6.1 percent Hispanic, 3.6 percent Other), after an average follow- up of 7.1 years are presented in Table 6.
| Event | Relative Risk CE vs. Placebo (95% nCI†) | CE n = 5,310 | Placebo N = 5,429 |
|---|---|---|---|
| Absolute Risk per 10,000 Women-Years | |||
| |||
CHD events‡ | 0.95 (0.78–1.16) | 54 | 57 |
Non-fatal MI‡ | 0.91 (0.73–1.14) | 40 | 43 |
CHD death‡ | 1.01 (0.71–1.43) | 16 | 16 |
All strokes‡ | 1.33 (1.15–1.68) | 45 | 33 |
Ischemic stroke‡ | 1.55 (1.19–2.01) | 38 | 25 |
1.47 (1.06–2.06) | 23 | 15 | |
Pulmonary embolism‡ | 1.37 (0.90–2.07) | 14 | 10 |
Invasive breast cancer‡ | 0.80 (0.62–1.04) | 28 | 34 |
Colorectal cancer¶ | 1.08 (0.75–1.55) | 17 | 16 |
Hip fracture‡ | 0.65 (0.45–0.94) | 12 | 19 |
0.64 (0.44–0.93) | 11 | 18 | |
0.58 (0.47–0.72) | 35 | 59 | |
0.71 (0.64–0.80) | 144 | 197 | |
1.08 (0.88–1.32) | 53 | 50 | |
1.04 (0.88–1.22) | 79 | 75 | |
Global IndexÞ | 1.02 (0.92–1.13) | 206 | 201 |
For those outcomes included in the WHI "global index" that reached statistical significance, the absolute excess risk per 10,000 women-years in the group treated with CE-alone was 12 more strokes, while the absolute risk reduction per 10,000 women-years was 7 fewer hip fractures. The absolute excess risk of events included in the "global index" was a non-significant 5 events per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality.
No overall difference for primary CHD events (nonfatal MI, silent MI and CHD death) and invasive breast cancer incidence in women receiving conjugated estrogens-alone compared to placebo was reported in final centrally adjudicated results from the estrogen-alone substudy, after an average follow-up of 7.1 years.
Centrally adjudicated results for stroke events from the estrogen-alone substudy, after an average follow-up of 7.1 years, reported no significant differences in distribution of stroke subtype or severity, including fatal strokes, in women receiving conjugated estrogens-alone compared to placebo. Estrogen-alone increased the risk for ischemic stroke, and this excess risk was present in all subgroups of women examined.
Timing of the initiation of estrogen-alone therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen-alone substudy, stratified by age, showed in women 50 to 59 years of age a non-significant trend toward reduced risk for CHD [hazard ratio (HR) 0.63 (95 percent CI, 0.36–1.09)] and overall mortality [HR 0.71 (95 percent CI, 0.46–1.11)].
14.6 Women's Health Initiative Memory Study
The WHIMS estrogen-alone ancillary study of WHI enrolled 2,947 predominantly healthy hysterectomized postmenopausal women 65 to 79 years of age (45 percent were 65 to 69 years of age, 36 percent were 70 to 74 years of age, and 19 percent were 75 years of age and older) to evaluate the effects of daily conjugated estrogens (0.625 mg)-alone on the incidence of probable dementia (primary outcome) compared to placebo.
After an average follow-up of 5.2 years, the relative risk of probable dementia for conjugated estrogens-alone versus placebo was 1.49 (95 percent CI, 0.83–2.66). The absolute risk of probable dementia for conjugated estrogens-alone versus placebo was 37 versus 25 cases per 10,000 women-years. Probable dementia as defined in this study included Alzheimer's disease (AD), vascular dementia (VaD) and mixed type (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women [see Warnings and Precautions (5.4) and Use in Specific Populations (8.5)].
PATIENT INFORMATIONDUAVEE® (DEW' AH-VEE) (CONJUGATED ESTROGENS/BAZEDOXIFENE)TABLETS
Patient Information DUAVEE® (DEW' ah-vee) (conjugated estrogens/bazedoxifene) Tablets
Read this Patient Information before you start taking DUAVEE and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.
What is the most important information I should know about DUAVEE?
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What is DUAVEE?
DUAVEE is a prescription medicine that contains a mixture of estrogens and bazedoxifene.
What is DUAVEE used for?
DUAVEE is used after menopause for women with a uterus to:
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- reduce moderate to severe hot flushes
Estrogens are hormones made by a woman's ovaries. The ovaries normally stop making estrogens when a woman is between 45 and 55 years old. This drop in body estrogen levels causes the "change of life" or menopause (the end of monthly menstrual periods). Sometimes both ovaries are removed during an operation before natural menopause takes place. The sudden drop in estrogen levels causes "surgical menopause."
When the estrogen levels begin dropping, some women get very uncomfortable symptoms, such as feelings of warmth in the face, neck, and chest, or sudden intense episodes of heat and sweating ("hot flashes" or "hot flushes"). In some women, the symptoms are mild, and they will not need to take medicines. In other women, symptoms can be more severe. - •
- help reduce your chances of developing osteoporosis (thin, weak bones)
If you use DUAVEE only to prevent osteoporosis due to menopause, talk with your healthcare provider about whether a different treatment or medicine without estrogens might be better for you.
DUAVEE should be taken for the shortest time possible and only for as long as treatment is needed.
You and your healthcare provider should talk regularly about whether you still need treatment with DUAVEE.
DUAVEE is not for use in children.
It is not known if DUAVEE is safe and effective in people with kidney problems.
Who should not take DUAVEE?
Do not take DUAVEE if you:
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- currently have or have had blood clots
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- are allergic to estrogens or bazedoxifene, the active ingredients in DUAVEE, or any of its ingredients.
See the list of ingredients in DUAVEE at the end of this leaflet. - •
- have unusual vaginal bleeding. Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause.
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- currently have or have had certain cancers. Estrogens may increase the chances of getting certain types of cancers, including cancer of the breast or uterus. If you have or have had cancer, talk with your healthcare provider about whether you should use DUAVEE.
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- currently have or have had liver problems
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- have been diagnosed with a bleeding disorder
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- are pregnant. DUAVEE is not for pregnant women. If you think you may be pregnant, you should have a pregnancy test and know the results. Do not take DUAVEE if the test is positive and talk to your healthcare provider.
What should I tell my healthcare provider before taking DUAVEE?
Before you take DUAVEE, tell your healthcare provider if you:
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- have any unusual vaginal bleeding.
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- have any other medical conditions. Your healthcare provider may need to check you more carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures), diabetes, migraine, endometriosis, lupus, or problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood.
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- are going to have surgery or will be on bed rest. Your healthcare provider will let you know if you need to stop taking DUAVEE.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
Especially tell your healthcare provider if you take other hormonal medicines, including progestins or other medicines like DUAVEE. Ask your healthcare provider if you do not know if you take any of these medicines.
Some medicines may affect how DUAVEE works. DUAVEE may also affect how your other medicines work. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.
How should I take DUAVEE?
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- DUAVEE comes in a blister package.
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- Record the date you open the foil pouch in the space provided on the blister package label. Do not use if the blister package has been open for more than 60 days.
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- Take DUAVEE exactly as your healthcare provider tells you to take it.
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- Take 1 DUAVEE tablet at the same time each day.
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- DUAVEE should be swallowed whole.
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- Take DUAVEE with or without food.
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- You should not remove DUAVEE from the blister until right before you are ready to take it. Remove 1 tablet at a time from the blister package. Do not place DUAVEE in pill boxes or pill organizers.
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- If you miss a dose of DUAVEE, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose. Take the next dose at your regular time. Do not take 2 doses at the same time unless your healthcare provider tells you to. If you are not sure about your dosing, call your healthcare provider.
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- If you take a calcium or vitamin D supplement, you may take it at the same time you take DUAVEE.
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- If you take too much DUAVEE, call your healthcare provider. Symptoms of taking too much DUAVEE include:
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What are the possible side effects of DUAVEE?
Side effects are grouped by how serious they are and how often they happen when you are treated.
Serious side effects include:
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- blood clots
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- stroke
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- heart attack
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- cancer of the lining of the uterus
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- breast cancer
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- cancer of the ovary
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- dementia
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- gallbladder problems
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- loss of vision
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- high blood pressure
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- increased fats in your blood
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- liver problems
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- thyroid problems
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- fluid retention
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- low calcium
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- swelling of your mouth or tongue
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- worsening of other medical problems such as asthma, diabetes, epilepsy, migraines, a genetic problem called porphyria, lupus and liver problems
Call your healthcare provider right away if you get any of the following warning signs, or any other unusual symptoms that concern you:
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- new breast lumps
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- unusual vaginal bleeding
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- changes in vision or speech
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- sudden new severe headaches
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- severe pains in your chest or legs with or without shortness of breath, weakness and fatigue
Less serious, but common side effects include:
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- muscle spasms
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- nausea
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- diarrhea
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- upset stomach
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- abdominal pain
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- throat pain
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- dizziness
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- neck pain
These are not all the possible side effects of DUAVEE. For more information, ask your healthcare provider or pharmacist. Tell your healthcare provider if you have any side effects that bother you or do not go away.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
What can I do to lower my chances of a serious side effect with DUAVEE?
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- Talk with your healthcare provider regularly about whether you should continue taking DUAVEE.
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- See your healthcare provider right away if you get vaginal bleeding while taking DUAVEE.
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- Have a pelvic exam, breast exam and mammogram (breast X-ray) every year unless your healthcare provider tells you something else.
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- If members of your family have had breast cancer or if you have ever had breast lumps or an abnormal mammogram, you may need to have breast exams more often.
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- If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or if you use tobacco, you may have higher chances of getting heart disease.
Ask your healthcare provider for ways to lower your chances of getting heart disease.
How do I store DUAVEE?
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- Store DUAVEE at room temperature between 68°F to 77°F (20°C to 25°C).
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- Keep DUAVEE in the blister until you are ready to take it to protect the tablet from moisture.
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- Do not place DUAVEE in pill boxes or pill organizers.
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- After opening the foil pouch the DUAVEE blisters come in, DUAVEE must be used within 60 days.
Keep DUAVEE and all other medicines out of the reach of children.
General information about the safe and effective use of DUAVEE
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use DUAVEE for a condition for which it was not prescribed. Do not give DUAVEE to other people, even if they have the same symptoms you have. It may harm them.
This Patient Information summarizes the most important information about DUAVEE. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about DUAVEE that is written for health professionals.
What are the ingredients in DUAVEE?
Active Ingredients: conjugated estrogens and bazedoxifene. Conjugated estrogens are a mixture of sodium estrone sulfate and sodium equilin sulfate and other components, including sodium sulfate conjugates, 17α-dihydroequilin, 17α-estradiol, and 17β-dihydroequilin.
Inactive Ingredients: calcium phosphate tribasic, hydroxypropyl cellulose, microcrystalline cellulose, powdered cellulose, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, sucrose, ascorbic acid, sucrose palmitic acid ester, hydroxyethylcellulose, titanium dioxide, red iron oxide, yellow iron oxide, black iron oxide, povidone, polydextrose, maltitol, poloxamer 188, propylene glycol, isopropyl alcohol.
This Patient Information has been approved by the U.S. Food and Drug Administration.
This product's labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com or call 1-800-438-1985.
LAB-0583-6.0
Revised December 2022
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